Active Targeting Drug Delivery Research Articles

Recent advances in sialic acid-based active targeting chemoimmunotherapy promoting tumor shedding: a systematic review.

Tumors have always been a major public health concern worldwide, and attempts to look for effective treatments have never ceased. Sialic acid is known to be a crucial element for tumor development and its receptors are highly expressed on tumor-associated immune cells, which perform significant roles in establishing the immunosuppressive tumor microenvironment and further boosting tumorigenesis, progression, and metastasis. Obviously, it is essential to consider sophisticated crosstalk between tumors, the immune system, and preparations, and understand the links between pharmaceutics and immunology. Sialic acid-based chemoimmunotherapy enables active targeting drug delivery via mediating the recognition between the sialic acid-modified nano-drug delivery system represented by liposomes and sialic acid-binding receptors on tumor-associated immune cells, which inhibit their activity and utilize their homing ability to deliver drugs. Such a "Trojan horse" strategy has remarkably improved the shortcomings of traditional passive targeting treatments, unexpectedly promoted tumor shedding, and persistently induced robust immunological memory, thus highlighting its prospective application potential for targeting various tumors. Herein, we review recent advances in sialic acid-based active targeting chemoimmunotherapy to promote tumor shedding, summarize the current viewpoints on the tumor shedding mechanism, especially the formation of durable immunological memory, and analyze the challenges and opportunities of this attractive approach.

Pluronic-Based Nanoparticles for Delivery of Doxorubicin to the Tumor Microenvironment by Binding to Macrophages.

The active targeting drug delivery system based on special types of endogenous cells such as macrophages has emerged as a promising strategy for tumor therapy, owing to its tumor homing property and biocompatibility. In this work, the active tumor-targeting drug delivery system carrying doxorubicin-loaded nanoparticles (DOX@MPF127-MCP-1, DMPM) on macrophage (RAW264.7) surfaces via the mediation of interaction with the CCR2/MCP-1 axis was exploited. Initially, the amphiphilic block copolymer Pluronic F127 (PF127) was carboxylated to MPF127 at the hydroxyl terminus. Subsequently, MPF127 was modified with MCP-1 peptide to prepare MPF127-MCP-1 (MPM). The DOX was wrapped in MPM to form DMPM nanomicelles (approximately 100 nm) during the self-assembly process of MPM. The DMPM spontaneously bound to macrophages (RAW264.7), which resulted in the construction of an actively targeting delivery system (macrophage-DMPM, MA-DMPM) in vitro and in vivo. The DOX in MA-DMPM was released in the acidic tumor microenvironment (TME) in a pH-responsive manner to increase DOX accumulation and enhance the tumor treatment effect. The ratio of MA-DMPM homing reached 220% in vitro compared with the control group, indicating that the MA-DMPM was excellently capable of tumor-targeting delivery. In in vivo experiments, nonsmall cell lung cancer cell (NCI-H1299) tumor models were established. The results of the fluorescence imaging system (IVIS) showed that MA-DMPM demonstrated tremendous tumor-targeting ability in vivo. The antitumor effects of MA-DMPM in vivo indicated that the proportion of tumor cell apoptosis in the DMPM-treated group was 63.33%. The findings of the tumor-bearing mouse experiment proved that MA-DMPM significantly suppressed tumor cell growth, which confirmed its immense potential and promising applications in tumor therapy.

Anti-Netrin-1 decorated nanoparticles combined with chemotherapy for the treatment of triple-negative breast cancer

Nanoparticle's success as drug delivery systems for cancer treatment has been achieved through passive targeting mechanisms. However, tumor heterogeneity and rapid drug clearance limit the treatment efficacy. Improved outcomes and selective drug release can be achieved by grafting ligands at the surface of nanocarriers that bind molecules overexpressed in the tumor microenvironment (TME). In this work, we developed a docetaxel-loaded nanoemulsions (NEs) binding an anti-netrin-1 monoclonal antibody (NP137) to selectively target the netrin-1 protein overexpressed in many different tumors. The goal is to refine a combined approach utilizing NP137 and docetaxel as an improved tumor-targeting chemotherapeutic agent for addressing triple-negative breast cancer (TNBC). Several factors have been considered for the optimization of the active targeted drug delivery system via the click-chemistry conjugation, as the impact of PEGylated surfactant that stabilize the NEs shell on conjugation efficiency, cytocompatibility with EMT6 cell line and colloidal stability over time of NEs. Results showed that a 660 Da PEG chain length contributed to NEs colloidal stability and had no impact on cell viability or on the antibody binding ability for its ligand after surface conjugation. Moreover, docetaxel was encapsulated into the oily core of NEs, with an encapsulation efficiency of 70 %. To validate our treatment strategy in vivo, the 4T1 murine breast cancer model was used. As a result, the comparison of active-targeted and non-targeted NEs revealed that only active-targeted NE could decrease the tumor growth rate.

Recent Advances in Targeted Drug Delivery Strategy for Enhancing Oncotherapy.

Targeted drug delivery is a precise and effective strategy in oncotherapy that can accurately deliver drugs to tumor cells or tissues to enhance their therapeutic effect and, meanwhile, weaken their undesirable side effects on normal cells or tissues. In this research field, a large number of researchers have achieved significant breakthroughs and advances in oncotherapy. Typically, nanocarriers as a promising drug delivery strategy can effectively deliver drugs to the tumor site through enhanced permeability and retention (EPR) effect-mediated passive targeting and various types of receptor-mediated active targeting, respectively. Herein, we review recent targeted drug delivery strategies and technologies for enhancing oncotherapy. In addition, we also review two mainstream drug delivery strategies, passive and active targeting, based on various nanocarriers for enhancing tumor therapy. Meanwhile, a comparison and combination of passive and active targeting are also carried out. Furthermore, we discuss the associated challenges of passive and active targeted drug delivery strategies and the prospects for further study.

Glucosamine-Modified Reduction-Responsive Polymeric Micelles for Liver Cancer Therapy.

In this work, glucose transporter-1 (GLUT-1) and glutathione (GSH) over-expression in liver cancer was utilized to design a reduction-responsive and active targeting drug delivery system AG-PEG-SS-PCL (APSP) for the delivery of sorafenib (SF). The SF-APSP micelles were prepared using the thin film hydration method and characterized by various techniques. In vitro release experiments showed that the cumulative release of SF-APSP micelles in the simulated tumor microenvironment (pH 7.4 with GSH) reached 94.76 ± 1.78% at 48 h, while it was only 20.32 ± 1.67% in the normal physiological environment (pH 7.4 without GSH). The in vitro study revealed that glucosamine (AG) enhanced the antitumor effects of SF, and SF-APSP micelles inhibited proliferation by targeting HepG2 cells and suppressing cyclin D1 expression. The in vivo antitumor efficacy study further confirmed that the SF-APSP micelles had excellent antitumor effects and better tolerance against nude mouse with HepG2 cells than other treatment groups. All in all, these results indicated that SF-APSP micelles could be a promising drug delivery system for anti-hepatoma treatment.

Platelets and platelet-derived vesicles as an innovative cellular and subcellular platform for managing multiple sclerosis.

Multiple sclerosis (MS) is a progressive inflammatory autoimmune disease that involves young individuals. The drug delivery systems now are available for this disease have chronic and non-targeted effects on the patients. Because of the presence of BBB (blood-brain-barrier), their concentration in the CNS (central nervous system) is low. Because of this flaw, it is critical to use innovative active targeted drug delivery methods. Platelets are blood cells that circulate freely and play an important role in blood hemostasis. In this review, we emphasize the various roles of activated platelets in the inflammatory condition to recruit other cells to the injured area and limit inflammation. Besides, the activated platelets in the different stages of the MS disease play a significant role in limiting the progression of inflammation in the peripheral area and CNS. This evidence indicates that a platelet-based drug delivery system can be an efficient biomimetic candidate for drug targeting to the CNS and limiting the inflammation in the peripheral and central areas for MS therapy.

A Star-Shaped Copolymer with Tetra-Hydroxy-Phenylporphyrin Core and Four PNIPAM-b-PMAGA Arms for Targeted Photodynamic Therapy.

The novel thermosensitive star-shaped tetra-hydroxy-phenylporphyrin-cored (THPP) double hydrophilic poly(N-isopropylacrylamide)-b-poly(methylacrylamide glucose) block copolymers (THPP-(PNIPAM-b-PMAGA)4) were synthesized via the reversible addition-fragmentation chain transfer (RAFT) polymerization. Notably, the low critical solution temperatures (LCSTs) of THPP-(PNIPAM-b-PMAGA)4 were above normal body temperature (37 °C) which depended on the hydrophilic PMAGA contents of copolymers. When the temperature was higher than the LCST of the copolymer, the copolymer could be neutralized into micelles in aqueous and could be coated with antitumor drugs and released around tumor cells. The MTT study indicated that THPP-(PNIPAM-b-PMAGA)4 had a low toxicity to L929 and HeLa cells in the absence of light. However, THPP-(PNIPAM-b-PMAGA)4 showed a high toxicity with HeLa cells under light irradiation which could be used as a potential photosensitizer for photodynamic therapy (PDT). In addition, THPP-(PNIPAM-b-PMAGA)4 showed specific a recognition function with Concanavalin A (Con A) to achieve active targeted drug delivery. This work provides a new approach for the development of tumor targeting and chemotherapy/PDT.

Niosomes Functionalized with a Synthetic Carbohydrate Binding Agent for Mannose-Targeted Doxorubicin Delivery.

Niosomes are a potential tool for the development of active targeted drug delivery systems (DDS) for cancer therapy because of their excellent behaviour in encapsulating antitumorals and the possibility to easily functionalise their surface with targeting agents. Recently, some of us developed a synthetic carbohydrate binding agent (CBA) able to target the mannosidic residues of high-mannose-type glycans overexpressed on the surface of several cancer cell lines, promoting their apoptosis. In this article, we modified the structure of this mannose receptor to obtain an amphiphilic analogue suitable for the functionalization of doxorubicin-based niosomes. Several niosomal formulations and preparation methods were investigated deeply to finally obtain functionalized niosomes suitable for parental administration, which were stable for over six months and able to encapsulate up to 85% of doxorubicin (DOXO). In vitro studies, carried out towards triple-negative cancer cells (MDA-MB231), overexpressing high-mannose-type glycans, showed a cytotoxic activity comparable to that of DOXO but with an appreciable increment in apoptosis given by the CBA. Moreover, niosomal formulation was observed to reduce doxorubicin-induced cytotoxicity towards normal cell lines of rat cardiomyocytes (H9C2). This study is propaedeutic to further in vivo investigations that can aim to shed light on the antitumoral activity and pharmacokinetics of the developed active targeted DDS.

IgG Fc Affinity Ligands and Their Applications in Antibody-Involved Drug Delivery: A Brief Review

Antibodies are not only an important class of biotherapeutic drugs, but also are targeting moieties for achieving active targeting drug delivery. Meanwhile, the rapidly increasing application of antibodies and Fc-fusion proteins has inspired the emerging development of downstream processing technologies. Thus, IgG Fc affinity ligands have come into being and have been widely exploited in antibody purification strategies. Given the high binding affinity and specificity to IgGs, binding stability in physiological medium conditions, and favorable toxicity and immunogenicity profiles, Fc affinity ligands are gradually applied to antibody delivery, non-covalent antibody-drug conjugates or antibody-mediated active-targeted drug delivery systems. In this review, we will briefly introduce IgG affinity ligands that are widely used at present and summarize their diverse applications in the field of antibody-involved drug delivery. The challenges and outlook of these systems are also discussed.

The design strategy for pillararene based active targeted drug delivery systems.

Pillararenes have columnar architectures with electron-rich cavities to endow themselves with unique host-guest complexation capability. Easy structural modifiability facilitates them to be used in many applications. Currently, pillararene based drug delivery systems (DDSs) have been developed as a powerful tool for precise diagnosis and treatment of cancer. Various functional guest molecules could be integrated with pillararenes to construct nanomaterials for cancer chemotherapy, phototherapy and chemodynamic therapy. In order to improve cancer therapy efficacy, active targeted DDSs have become particularly important. Benefiting from the good host-guest properties and structural variability of pillararenes, tumor targeting groups could be easily introduced into pillararene based DDSs to realize precise drug delivery at tumor sites. In this feature article, we provide a comprehensive summary of the present design strategy for pillararene based active targeted DDSs, which can be classified into three types namely host-guest complexation, charge reversal and targeted group modified pillararenes. Some important examples are selected to for a detailed discussion on their respective strengths and weaknesses.

F3‐functionalized nanoscale metal–organic frameworks for tumor‐targeting combined chemotherapy and chemodynamic therapy

AbstractNanoscale metal–organic frameworks (nMOFs) have attracted much attention as emerging porous materials as drug delivery carriers. Appropriate surface modification of them can greatly improve stability and introduce biocompatibility and cancer targeting functionality into drug delivery systems. Herein, we prepared nano‐sized MIL‐101(Fe)‐N3 and loaded anticancer drug doxorubicin (DOX) into it. The synthetic polymer layer Alkyne‐PLA‐PEG was then attached to the F3 peptide (labeled as Alkyne‐PLA‐PEG‐F3), and the surface of DOX/MIL‐101(Fe)‐N3 was covalently modified with it to obtain DOX/MIL‐101‐PLA‐PEG‐F3. Nano‐sized MIL‐101(Fe)‐N3 has high drug loading capacity and the modification of MIL‐101(Fe)‐N3 by polymer Alkyne‐PLA‐PEG not only improved the dispersion, but also avoided the sudden release of the drugs and increased the biocompatibility of nanocarriers. The F3 peptide introduced into the nanocarriers also enabled it to specifically target tumor tissues and achieved active targeted drug delivery. As a nucleolin‐mediated endocytosis drug delivery system, DOX/MIL‐101‐PLA‐PEG‐F3 can not only deliver anticancer drugs to tumors accurately, but also participate in Fenton‐like reaction to generate hydroxyl radicals (•OH) for chemodynamic therapy (CDT), thus enabling combination therapy. It holds great promise as drug candidates to reduce systemic toxicity and improve the efficacy of cancer treatment.

PH-Responsive PEGylated Niosomal Nanoparticles as an Active-Targeting Cyclophosphamide Delivery System for Gastric Cancer Therapy.

A PEGylated niosomal formulation of cyclophosphamide (Nio-Cyclo-PEG) was prepared using a central composite design and characterized in terms of drug loading, size distribution, and average size. The stability of formulations was also studied at different conditions. In vitro cytotoxicity of drug delivery formulations was assessed on gastric cancer cells using MTT assay. The mechanism of cytotoxicity was studied at the transcriptional level by real-time PCR on Caspase3, Caspase9, CyclinD, CyclinE, MMP-2, and MMP-9 genes, while apoptosis was investigated with flow cytometry. The anti-metastatic property was evaluated using the scratch method. Propidium iodide staining was used to study the cell cycle. The results indicated that the as-designed nanocarrier exhibited a controlled drug release pattern with improved nanoparticle stability. It was found that the living cancer cells treated with Nio-Cyclo-PEG showed a significant decrease in number when compared with the niosomal carrier without PEG (Nio-Cyclo) and free drug (Cyclo). Moreover, the drug-loaded nanocarrier induced planned death (apoptosis) in the cancer cells through the regulation of Caspase3, Caspase9, CyclinD, CyclinE, MMP-9, and MMP-2 gene expression, indicating that the Nio-Cyclo-PEG formulation could significantly inhibit the cell cycle at the sub G1 phase as well as prevent the migration of cancer cells. In conclusion, Nio-Cyclo-PEG as developed in this study could serve as an active-targeting drug delivery nanocarriers for gastric cancer therapy with high efficacy and minimal side effects on healthy tissues/cells.

Targeted drug delivery nanocarriers based on hyaluronic acid-decorated dendrimer encapsulating gold nanoparticles for ovarian cancer therapy

The integration of active targeted drug delivery and stimuli-dependent drug release in one nanocarrier holds great potential for enhancing anticancer efficacy and limiting adverse effects. Herein, we prepared hyaluronic acid (HA)-modified dendrimer encapsulating gold nanoparticles (AuDEN) as active targeted drug delivery nanocarriers for effective treatment of ovarian cancer. Resulting nanocarriers could load doxorubicin (DOX) efficiently with high drug loading content and chemical stability through self-assembly of thiolated DOX on the Au surface of nanocarriers. Surface-exposed HA in these nanocarriers made it possible to deliver the nanodrug (denoted as HA-AuDEN-DOX) to cluster determinant 44-overexpressing cancer cells. DOX was then released in an acidic tumor microenvironment with a high glutathione (GSH) concentration. HA-AuDEN-DOX greatly delayed DOX release under a physiological condition (pH 7.4), whereas a burst release of DOX was observed under an acidic condition (pH 5.6) in the presence of GSH. In comparison with free-DOX, HA-AuDEN-DOX showed enhanced cytotoxicity to cancer cells, demonstrating an enhanced cellular uptake and a superior IC50 value of 2.72 μM. Importantly, cellular internalization pathways of HA-AuDEN-DOX to SK-OV-3 cells were estimated, showing the following quantitative values: receptor-mediated endocytosis, 31.5%; caveolae-mediated endocytosis, 28.7%; macropinocytosis, 26.1%. In vivo anticancer activity and biodistributions of HA-AuDEN-DOX were evaluated with an SK-OV-3 xenograft tumor-bearing mouse model, revealing an outstanding treatment-control (T/C) ratio of 66% (about four times higher than free-DOX treated value of 16.4%) for tumor growth inhibition. Compared to the administration of free-DOX, HA-AuDEN-DOX showed a decreased cardiotoxic effect. Furthermore, immunohistochemical study of Ki67 antigen expression revealed the effective suppression of cell proliferation in xenograft ovarian tumor tissues after HA-AuDEN-DOX treatment. These features highlight a promising application of HA-AuDEN-DOX for the treatment of ovarian cancer with cluster determinant 44 overexpression.

Aptamer-Functionalized Iron-Based Metal-Organic Frameworks (MOFs) for Synergistic Cascade Cancer Chemotherapy and Chemodynamic Therapy.

Hypoxia-activated prodrugs (HAPs) with selective toxicity in tumor hypoxic microenvironments are a new strategy for tumor treatment with fewer side effects. Nonetheless, the deficiency of tumor tissue enrichment and tumor hypoxia greatly affect the therapeutic effect of HAPs. Herein, we design an active targeted drug delivery system driven by AS1411 aptamer to improve the tumor tissue enrichment of HAPs. The drug delivery system, called TPZ@Apt-MOF (TA-MOF), uses iron-based MOF as a carrier, surface-modified nucleolin aptamer AS1411, and the internal loaded hypoxia activation prodrug TPZ. Compared with naked MOF, the AS1411-modified MOF showed a better tumor targeting effect both in vitro and in vivo. MOF is driven by GSH to degrade within the tumor, producing Fe2+, and releasing the cargo. This process leads to a high consumption of the tumor protective agent GSH. Then, the Fenton reaction mediated by Fe2+ not only consumes the intracellular oxygen but also increases the intracellular production of highly toxic superoxide anions. This enhances the toxicity and therapeutic effect of TPZ. This study provides a new therapeutic strategy for cancer treatment.

The Application of Targeted Nanodrugs with Dual Responsiveness of PH and Ros in Preventing and Treating Vascular Restenosis.

In order to study the application of PH- and Ros-responsive targeted nanodrugs in preventing and treating vascular restenosis, a method based on pH-responsive and reactive oxygen species- (ROS-) responsive carrier materials synthesized in the early stage and rapamycin as a model drug was proposed. This method evaluated the therapeutic advantages of PH and Ros dual-responsive nanoparticles and the effect of dual-responsive active targeted drug delivery nanoparticles on vascular restenosis in vivo by comparing with nonresponsive PH or Ros single responsive nanotherapy. By optimizing the feed mass ratio of pH-responsive materials (ACD) and ROS-responsive materials (OCD), the best pH and ROS responsive nanoparticles were prepared. It has been proved that nanoparticles have ultrasmall volume (10–1000 nm) and can easily pass through the blood vessel wall without causing damage and have the characteristics of targeting and sustained release, so they are an ideal carrier for local administration. Nanoparticles as gene vectors have also achieved good results.

Microneedle-Mediated Biomimetic Cyclodextrin Metal Organic Frameworks for Active Targeting and Treatment of Hypertrophic Scars.

Due to the lack of a delivery system that actively targets hypertrophic scar fibroblasts (HSFs), it is difficult to concentrate the effects of drugs on hypertrophic scars (HSs). We recently discovered that the HSF membrane has a homologous targeting effect and developed an active targeted drug delivery system for the local treatment of HSs. A diphenyl carbonate cross-linked cyclodextrin metal organic framework (CDF) containing more than 26% (w/w) quercetin (QUE) was coated with a HSF membrane (QUE@HSF/CDF) and then dispersed in Bletilla striata polysaccharide (BSP)-fabricated dissolvable microneedles (BSP-MNs-QUE@HSF/CDF) for local administration. This biomimetic nanodrug delivery system improved efficacy on HSs by regulating Wnt/β-catenin and JAK2/STAT3 pathways and reducing the expression of collagens I and III in HS, and this performance was superior to those of systems without HSF functionalization or the assistance of microneedles. Additionally, we found that BSP has synergistic effects and the microneedles have higher mechanical strength and better physical stability than microneedles made of hyaluronic acid. This currently designed drug delivery strategy integrating biomimetic nanoparticles and dissolvable microneedles is promising for applications in the fields of skin disease treatment and cosmetics.

Lipid Polymeric Hybrid Nanoparticles: Formulation Techniques and Effects on Glioblastoma

Introduction: In the pharmaceutical industry, liposomes and polymeric nanoparticles are the two most commonly studied delivery vehicles. A new technique uses lipid-polymeric hybrid nanoparticles (LPHNPs) with a polymeric core, and a shell made up of lipid-lipid-PEG lipids. They have properties which complement polymer nanoparticles and liposomes, and they have the potential to improve the physical stability and biocompatibility of the active pharmaceutical ingredient encapsulated in them. Evaporating the solvent from a dual-phase solution containing lipid and polymer is one of the most effective methods for producing the lipid polymeric hybrid nanoparticles. The LPHNPs applications has also been significantly expanded to include combinational and active targeted drug delivery, as well as delivery of genetic materials, vaccines, and diagnostic imaging agents, in addition to single drug delivery for anticancer therapy, like Glioblastoma. Main goal: The main agenda of this compilation was to address the effects of LPHNPs on Glioblastoma treatment. This compilation also highlights some of the formulation techniques and issues that arise during the preparation of LPHNPs. This review also discusses recent developments in core-shell lipid-polymer hybrid nanoparticles, which were conferred in considerable detail later in this article. Conclusion: The main issue which arises while using nanoparticles with polymer is entrapment efficiency. Because of their hybrid components, LPHNPs have proven to solve this problem to a large extent. The recent research trends suggest that lipid polymeric hybrid nanoparticles will prove to be highly effective or productive in treating diseases such as Glioblastoma.

Surface Ligand Valency and Immunoliposome Binding: when More Is Not Always Better.

Nano-drug delivery systems are designed to contain surface ligands including antibodies for "active targeting". The number of ligands on each nanoparticle, known as the valency, is considered a critical determinant of the "targeting" property. We sought to understand the correlation between valency and binding properties using antibody conjugated liposomes, i.e. immunoliposomes (ILs), as the model. Anti-CD3 Fab containing a terminal cysteine residue were conjugated to DSPE-PEG-maleimide and incubated with preformed liposomes at 60°C. The un-incorporated antibodies were removed and the obtained ILs were characterized to contain in average 2-22 copies of anti-CD3 Fabs per liposome. The Biolayer Interferometry (BLI) probe surface was coated with various densities of CD3 epsilon&delta heterodimer (CD3D/E) to imitate different CD3 expression levels on target cells. The inference wavelength shifts upon anti-CD3 liposome binding were monitored and analyzed. The data indicated ILs may bind either monovalently or multivalently, determined mainly by the surface ligand density rather than the ILs antibody valency. The ILs valency indeed correlated with the dissociation rate constant (Koff), but not with the association rate constant (Kon). Their binding capabilities also did not necessarily increase with the surface anti-CD3 valency. We proposed a model for understanding the binding properties of ILs with different ligand valencies. The binding mode may change when the targeted surfaces had different antigen densities. The model should be important for the designing and optimization of active targeting drug delivery systems to fit different applications.

A simple, fast, and orientation-controllable technology for preparing antibody-modified liposomes

Modification with antibodies is a useful strategy for the delivery of nanoparticles to target cells. However, the complexity of the required chemical modifications makes them time-consuming and low efficiency, and the orientation of the antibody is challenging to control. To develop a simple, fast, effective, and orientation-controllable technology, we employed staphylococcal protein A, which can bind to the Fc region of antibodies, as a tool for conjugating antibodies to nanoparticles. Specifically, we modified the C-domain dimer of protein A to contain a lysine cluster to create a molecule, DPACK, that would electrostatically bind to anionic liposomes. Using this protein, antibody-modified liposomes can be prepared in 35 min with two steps: (1) interaction of DPACK with liposomes and (2) interaction of an antibody with DPACK-modified liposomes. Binding efficiencies of DPACK with liposomes and IgG with DPACK-modified liposomes were 75% and 72–84%, respectively. Uptake of liposomes modified with anti-epidermal growth factor receptor (EGFR) antibodies via DPACK by EGFR-expressing cancer cells was significantly higher than that of unmodified liposomes, and the liposomes accumulated in tumors and colocalized with EGFR. This simple, fast, effective and orientation-controllable technology for preparing antibody-modified liposomes will be useful for active targeting drug delivery.

Effect of Malt-PEG-Abz@RSL3 micelles on HepG2 cells based on NADPH depletion and GPX4 inhibition in ferroptosis

Ferroptosis is a regulated cell death pathway which depends on iron. Ferroptosis can be induced by limiting intracellular glutathione (GSH) synthesis, or inhibiting the activity of GPX4, or increasing intracellular accumulation of PE-AA-OOH, all of which involve NADPH. Therefore, NADPH depletion, excessive PE-AA-OOH, and GPX4 deficiency are generally considered to be the main characteristics of ferroptosis. In this research, the novel self-assembly nanomicelles modified by maltose ligand (Malt-PEG-Abz@RSL3) with superior nano characteristics were designed and fabricated. Malt-PEG-Abz@RSL3 micelles achieved active targeted drug delivery due to the high expression of glucose transporter (GLUT) and high uptake by HepG2 cells. Maltose-polyethylene glycol broke to release RSL3 for inhibiting GPX4 activity when Malt-PEG-Abz@RSL3 micelles entered the cells. Meanwhile, key coenzyme NADPH that participated in synthesis of GSH and Trx(SH)2 was depleted by azobenzene moiety, resulting in decreasing GSH and Trx(SH)2, which dually induced ferroptosis in tumor cells and promoted cell apoptosis.